Targeting protease inhibitors to the gut-associated lymphoid tissues for improved treatment of HIV/AIDS
"Gut-associated lymphoid tissue (GALT) is an anatomical reservoir of HIV, setting a barrier for strategies aimed at HIV eradication. From a therapeutic perspective, limited data exist on the pharmacokinetics and pharmacodynamics of antiretrovirals within GALT. It has been proposed that incomplete immune reconstitution within GALT could be due to low levels of drugs within this compartment. Targeting the intestinal lymphatics is challenging because only a limited proportion of absorbed drug is distributed into the lymphatic system from systemic circulation. On the other hand, intestinal lymphatic transport following oral administration results in extremely high concentrations of the drug in the intestinal lymphatics. Therefore, the delivery of protease inhibitors to the intestinal lymphatics has potential to improve substantially the treatment of HIV/AIDS.
The aim of this PhD project is to improve the treatment outcomes of HIV/AIDS by targeting the antiretroviral drugs specifically to the GALT. This will be achieved by design and synthesis of prodrugs of protease inhibitors with high potential for intestinal lymphatic transport. Intestinal lymphatic transport is governed by association of the molecules with chylomicrons in the enterocytes. An in silico model for association of drugs with chylomicrons will be used to evaluate the intestinal lymphatic transport potential of candidate molecules. Modifications of structures of protease inhibitors will be designed to yield prodrugs that possess the appropriate physicochemical properties required for efficient intestinal lymphatic transport following oral administration. The purified prodrugs will be assessed for the intestinal lymphatic potential by their degree of association with artificial chylomicrons-like emulsion (Intralipid®), and with natural chylomicrons separated from blood of human volunteers.
The pharmacokinetics and GALT biodistribution of the synthesised prodrugs and the corresponding active drugs will be assessed in vivo in a rat model. The antiviral activity of the drugs and prodrugs in the form that they appear in the GALT (associated with lipoproteins) will be assessed in vitro.
Finally, the in vivo efficacy of the proposed targeting approach will be assessed in a humanized mouse model of HIV infection.
Applications are invited from self-funded students.
The project will be co-supervised by Dr Pavel Gershkovich and Professor Peter Fischer in the University of Nottingham, UK. In addition, the project will benefit from collaborative support of Centre for Excellence in HIV/AIDS in the University of British Columbia, Vancouver, Canada. The prospective student will have an opportunity to travel between the UK and Canadian sites.
For informal inquiries please contact Dr Pavel Gershkovich ([email protected]).
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